Toll-Like Receptor 4 Mediates Alcohol-Induced Steatohepatitis Through Bone Marrow-Derived and Endogenous Liver Cells in Mice
- 4 April 2011
- journal article
- Published by Wiley in Alcohol: Clinical and Experimental Research
- Vol. 35 (8), 1509-1518
- https://doi.org/10.1111/j.1530-0277.2011.01487.x
Abstract
Background: Excessive alcohol intake causes an increase in intestinal permeability that induces translocation of gut‐derived lipopolysaccharide (LPS) to the portal vein. Increased LPS in the portal vein stimulates Kupffer cells through Toll‐like receptor (TLR) 4 in the liver. Activated TLR4 signaling in Kupffer cells induces various inflammatory mediators including TNF‐α, IL‐1β, and reactive oxygen species, resulting in liver injury. Hepatic stellate cells (HSCs) also express TLR4. This study investigates whether TLR4 on bone marrow (BM)‐derived cells, including Kupffer cells, or non–BM‐derived endogenous liver cells, including HSCs, contributes to the progression of alcohol‐induced steatohepatitis and fibrogenesis in mice. Methods: TLR4 BM chimera (wild‐type [WT] mice with TLR4−/− BM or TLR4−/− mice with WT BM) were generated by the combination of liposomal clodronate injection with whole body irradiation and BM transplantation, followed by treatment with intragastric alcohol feeding. Results: WT mice transplanted with WT BM exhibited liver injury, steatosis, inflammation, and a fibrogenic response. Conversely, TLR4−/− mice with TLR4−/− BM displayed less steatosis, liver injury, and inflammation. Notably, steatosis, macrophage infiltration, and alanine aminotransferase levels in both TLR4‐chimeric mice showed intermediate levels between WT mice transplanted with WT BM and TLR4−/− mice transplanted with TLR4−/− BM. Hepatic mRNA expression of fibrogenic markers (collagen α1(I), TIMP1, TGF‐β1) and inflammatory cytokines (IL‐1β, IL‐6) were markedly increased in WT mice with WT BM, but there was less of an increase in both TLR4‐chimeric mice and in TLR4−/− mice transplanted with TLR4−/− BM. Conclusions: TLR4 signaling in both BM‐derived and non–BM‐derived liver cells is required for liver steatosis, inflammation, and a fibrogenic response after chronic alcohol treatment.Keywords
This publication has 42 references indexed in Scilit:
- Enteric dysbiosis associated with a mouse model of alcoholic liver diseaseJournal of Hepatology, 2010
- Toll-like Receptor 4 and Hepatic FibrogenesisSeminars in Liver Disease, 2010
- Alcoholic liver disease and the gut-liver axisWorld Journal of Gastroenterology, 2010
- CCR2 promotes hepatic fibrosis in miceJournal of Hepatology, 2009
- Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker NanogProceedings of the National Academy of Sciences of the United States of America, 2009
- The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88Journal of Hepatology, 2008
- Hepatic macrophage iron aggravates experimental alcoholic steatohepatitisAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
- Regulation of macrophage activation in alcoholic liver diseaseJournal of Gastroenterology and Hepatology, 2007
- The role of TGFβ1 in initiating hepatic stellate cell activation in vivoJournal of Hepatology, 1999
- Beef Fat Prevents Alcoholic Liver Disease in the RatAlcohol: Clinical and Experimental Research, 1989